Excess weight and obesity currently constitute one of the major public health concerns due to their increasing prevalence and comorbidities. These include, for example, dyslipidemia, diabetes, cardiovascular diseases, arteriosclerosis, hepatic steatosis or fatty liver, metabolic syndrome, hypertension and some types of cancer.
Hepatic steatosis or non-alcoholic fatty liver is an alteration with a high degree of association with obesity and appears in up to 50% of obese individuals, both children and adults, constituting the main current liver disease. Likewise, dyslipidemias (hypertriglyceridemia and hypercholesterolemia) are associated with obesity, Type 2 diabetes mellitus and hypertension, and constitute the main risk factor for cardiovascular pathologies. Lowering triglyceride and cholesterol levels in the serum of subjects with abnormally high levels of these biochemical parameters is beneficial and, particularly, lowering LDL cholesterol, as it is considered a clear risk factor for cardiovascular pathologies and a decrease therein is related to a reduction in morbidity and total mortality as a result of long-term cardiovascular pathologies. In this context, the liver plays an important role because it is the main organ principally responsible for maintaining cholesterol homeostasis (maintenance of physiological concentrations). The liver synthesizes 15% of novo cholesterol and this process is, in turn, regulated by dietary cholesterol. Cholesterol levels are maintained at a constant level by means of various mechanisms, including (i) regulation of the activity and concentration of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase enzyme, (ii) regulation of the acyl-CoA:cholesterol acyltransferase (ACAT) enzyme, which controls excess intracellular free cholesterol and its transformation into cholesterol esters, which is the form in which they are transported, and (iii) regulation of the expression of the hepatic LDL receptors which allow absorption of plasma cholesterol and reverse transport thereof by HDL. The cholesterol just created in the liver is initially released into the bloodstream in the form of very low-density lipoproteins (VLDL) and can contribute to the increase thereof. However, the liver also contributes to the elimination of blood cholesterol through several mechanisms: (i) conversion into bile acids, (ii) transport of excess cholesterol to the intestine for faecal excretion and (iii) conversion of VLDL to LDLc and TG, which shall be used as sources of energy for extra-hepatic tissues. Alterations in lipid metabolism that affect the blood lipid profile and their accumulation in peripheral tissues can also occur in non-obese subjects, preceding obesity, or occur for causes other than obesity, including those of genetic (e.g: congenital diseases), infectious (for example, viral hepatitis), self-immune or nutritional origin (for example, malnutrition) or those arising from other clinical situations or pharmacological treatments (for example, use of drugs).
Obesity is also considered a state of mild chronic inflammation, characterised in that there is a high production of cytokines, adipokines and other pro-inflammatory proteins in the adipose tissue and in other peripheral tissues and at systemic level, that contribute to the metabolic alterations which can be permanently suffered by these individuals, such as Type 2 diabetes mellitus and cardiovascular pathologies (Tilg y Moschen, 2006. Nat Rev Immunol., 6: 772-783). The inflammatory factors related to obesity and metabolic alterations include, most notably, pro-inflammatory cytosine TNF-α. In particular, TNF-α reduces the expression of the genes involved in the action of insulin (for example, that of the insulin receptor gene), attenuates insulin signalling and inhibits lipoprotein lipase activity stimulated by the insulin. This favours the development of insulin resistance and hepatic steatosis. The function of the pro-inflammatory cytokines in this process is also evident in the use of drugs based on anti-TNF-α to improve pathologies such as hepatic steatosis and Type 2 diabetes mellitus (Tilg y Moschen, 2006. Nat Rev Immunol., 6: 772-783).
Obesity is also characterised by alterations in the functions of various immune system cells, such as macrophages, dendritic cells and T cells, associated with reduced defenses against pathogens and other antigens, and with a higher risk of infections and post-operative complications. Adipose tissue macrophages have less phagocytic capability and reduced respiratory burst, which are processes involved in the innate immune system's response to infectious agents (Zhou et al., 2009. Proc Natl Acad Sci USA, 106(26): 10740-5.). Additionally, dendritic cells have reduced capability to stimulate T cells, which are involved in the adaptive immune response responsible, for example, for antibody production in vaccination and for memory T cell response to infection (Karlsson et al., 2010. J Immunol., 184:3127-33).
Social changes associated with the steady increase in intake of high-energy-dense food and a low level of physical activity are considered to be the main causes of the increase in global obesity rates. However, traditional treatments based on hypocaloric diets and increased physical activity are less effective at controlling obesity and, in general, lead to limited and temporary weight loss. Neither has the use of pharmacological strategies been satisfactory, as they entail side effects. Consequently, the search for new intervention strategies aimed at improving the treatment and enabling the prevention of these pathologies continues.
The microbiota that colonise the human intestine are considered a new factor involved in obesity and associated diseases through their capability to regulate the individual's metabolic and immunological functions (Sanz et al., 2010. Proc Nutr Soc, 14: 1-8.). In recent years, various studies have established an association between an increase in the proportion of members of the phylum Bacteroidetes and a thin phenotype or weight loss and, on the contrary, a decrease therein has been associated with an obese phenotype (Ley et al., 2006. Nature, 444: 1022-1023; Nadal et al., 2008. Int J Obes., 33(7): 758-67); however, direct evidence of the possible effect of strains of the genus Bacteroides or of strains of the species Bacteroides uniformis administered orally in obesity has not been provided. Patent WO/2008/076696 proposes the use of changes in the intestinal microbiota to diagnose obesity and modification thereof as a way of treating obesity by increasing the proportion of the phylum Bacteroidetes and reducing that of the phylum Firmicutes. However, these phylogenetic groups integrate more than 90 and 200 different species and subspecies, respectively, whose individual effects could be very different and contradictory. In fact, WO/2008/076696 does not prove that no specific species or strain of the phylum Bacteroides has a beneficial effect in this context and, on the contrary, the only species evaluated in animal models, Bacteroides thetaiotaomicron, causes increase in body weight and adipose tissue and insulin resistance (Samuel y Gordon. Proc Nati Acad Sci USA. 2006; 27; 103(26): 10011-6). Patent US 2009/01 10664A1 proposes the use of the genus Bacteroides in body weight loss, but administering the bacterium after cleansing or removing the components themselves from the intestinal tract, as opposed to the present invention. Additionally, this patent does not disclose the results of the effects of any species or strain of this genus on body weight.
Other strategies based on the use of certain food ingredients or supplements only partially address the problem of obesity or of the pathologies arising from alterations in lipid and glucose metabolism, as in the case of stanols and phytosterols, which only act by reducing absorption of dietary cholesterol, which is not the only cause of elevation in plasma cholesterol. Likewise, lipid-lowering drugs such as statins that inhibit endogenous cholesterol synthesis do not achieve the required effectiveness due to being monotherapies focused on a single mechanism of action.
Therefore, the problem of finding specific components of commensal intestinal microbiota which can be used to prevent and/or treat diseases such as excess weight, obesity and metabolic pathologies associated or not associated to obesity and related to alterations in lipid and glucose metabolism, such as for example dyslipidemia, hepatic steatosis, metabolic syndrome, insulin resistance, Type 2 diabetes mellitus, gestational diabetes, hypertension and cardiovascular pathologies, in a more suitable manner by acting jointly on the immune system and metabolism alterations, responsible for chronic pathologies, remains unsolved.